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1.  The Patterns of Drug and Alcohol Use and Associated Problems over 30 Years in 397 Men 
Background
Alcohol- and drug-use disorders (AUDs and SUDs) and their combination are relatively common, and often occur together. However, the relationships of potential early life correlates of alcohol and drug disorders to the combined diagnoses have rarely been evaluated in long-term prospective studies or in populations at high risk for one of these diagnoses but not the other.
Methods
Data were analyzed from 397males (half with an alcohol-dependent father) who had no AUDs or SUDs at age 20 and who were followed ~every five years for three decades. Early life correlates and the course of AUDs, SUDs, and combined disorders were evaluated for four groups of subjects based on subsequent alcohol and/or drug diagnoses.
Results
While the overall rates of the development of AUDs and SUDs were 41% and 21%, respectively, the rates of the second substance-related diagnosis were almost two-fold higher for individuals who had the first condition. Among potential risk factors, scores for externalizing traits were elevated for men with AUDs, SUDs, and their combination, but a low level of response (low LR) to alcohol was associated only with the risk for AUDs, even when observed in the context of SUDs. The same earlier life characteristics that related to AUDs and to SUDs also related to the combination of these diagnoses in the same person. Finally, in this prospective study subjects with both alcohol and drug use disorders had a more severe course than subjects with either condition alone.
Conclusions
This prospective evaluation of a group at high risk for AUDs confirmed the selective impact of the low LR on the risk for AUDs, the relationship of externalizing characteristics to both AUDs and SUDs, and confirmed the more severe clinical course for both conditions when seen together.
doi:10.1111/acer.12220
PMCID: PMC3830655  PMID: 23895676
alcoholism; drug dependence; comorbidity; level of response to alcohol; externalizing clinical course
2.  DSM-5 Cannabis Use Disorder: A Phenotypic and Genomic Perspective* 
Drug and alcohol dependence  2013;134:362-369.
Background
We explore the factor structure of DSM-5 cannabis use disorders, examine its prevalence across European- and African-American respondents as well as its genetic underpinnings, utilizing data from a genome-wide study of single nucleotide polymorphisms (SNPs). We also estimate the heritability of DSM-5 cannabis use disorders explained by these common SNPs.
Methods
Data on 3053 subjects reporting a lifetime history of cannabis use were utilized. Exploratory and confirmatory factor analyses were conducted to create a factor score, which was used in a genomewide association analysis. P-values from the single SNP analysis were examined for evidence of gene-based association. The aggregate effect of all SNPs was also estimated using Genome-Wide Complex Traits Analysis.
Results
The unidimensionality of DSM-5 cannabis use disorder criteria was demonstrated. Comparing DSM-IV to DSM-5, a decrease in prevalence of cannabis use disorders was only noted in European-American respondents and was exceedingly modest. For the DSM-5 cannabis use disorders factor score, no SNP surpassed the genome-wide significance testing threshold. However, in the European-American subsample, gene-based association testing resulted in significant associations in 3 genes (C17orf58, BPTF and PPM1D) on chromosome 17q24. In aggregate, 21% of the variance in DSM-5 cannabis use disorders was explained by the genomewide SNPs; however, this estimate was not statistically significant.
Conclusions
DSM-5 cannabis use disorder represents a unidimensional construct, the prevalence of which is only modestly elevated above the DSM-IV version. Considerably larger sample sizes will be required to identify individual SNPs associated with cannabis use disorders and unequivocally establish its polygenic underpinnings.
doi:10.1016/j.drugalcdep.2013.11.008
PMCID: PMC3943464  PMID: 24315570
Cannabis; DSM-5; GWAS; association; genetics; heritability
3.  A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks 
Human genetics  2013;132(10):1141-1151.
Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (> 50%) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N=2322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N=2593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1×10−6) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1×10−7), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2×10−7) and PLCL1 genes (p = 4.1×10−6) with increased maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p≤10−4) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2×10−3, 3×10−6), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.
doi:10.1007/s00439-013-1318-z
PMCID: PMC3776011  PMID: 23743675
Alcohol consumption; maximum number of alcoholic drinks; GWAS; COGA; SAGE
4.  Measurement invariance of DSM-IV alcohol, marijuana, and cocaine dependence between community-sampled and clinically over-selected studies 
Addiction (Abingdon, England)  2013;108(10):1767-1776.
Aims
To examine whether DSM-IV symptoms of substance dependence are psychometrically equivalent between existing community-sampled and clinically over-selected studies.
Participants
2476 adult twins born in Minnesota; 4121 unrelated adult participants from a case-control study of alcohol dependence.
Measurements
Lifetime DSM-IV alcohol, marijuana, and cocaine dependence symptoms and ever use of each substance.
Design
We fit a hierarchical model to the data, in which ever use and dependence symptoms for each substance were indicators of alcohol, marijuana, or cocaine dependence, which were in turn indicators of a multi-substance dependence factor. We then tested the model for measurement invariance across participant groups, defined by study source and participant sex.
Findings
The hierarchical model fit well among males and females within each sample (CFI>0.96, TLI>0.95, and RMSEA<0.04 for all), and a multi-group model demonstrated that model parameters were equivalent across sample- and sex-defined groups (∆CFI=0.002 between constrained and unconstrained models). Differences between groups in symptom endorsement rates could be expressed solely as mean differences in the multi-substance dependence factor.
Conclusions
Lifetime substance dependence symptoms fit a dimensional model well. Although clinically over-selected participants on average endorsed more dependence symptoms than community-sampled participants, the pattern of symptom endorsement was similar across groups. From a measurement perspective, DSM-IV criteria are equally appropriate for describing substance dependence across different sampling methods.
doi:10.1111/add.12187
PMCID: PMC3742679  PMID: 23651171
substance dependence; sampling comparison; sex differences; item response theory
5.  Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults 
Behavior genetics  2013;43(5):386-401.
Discrete time survival analysis (DTSA) was used to assess the age-specific association of event related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2938 adolescents and young adults ages 12 to 25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens.
doi:10.1007/s10519-013-9604-z
PMCID: PMC4110722  PMID: 23963516
alcoholism; CHRM2; survival analysis; ERO; genetics; adolescents
6.  DSM-5 Criteria for Substance Use Disorders: Recommendations and Rationale 
The American journal of psychiatry  2013;170(8):834-851.
Since DSM-IV was published in 1994, its approach to substance use disorders has come under scrutiny. Strengths were identified (notably, reliability and validity of dependence), but concerns have also arisen. The DSM-5 Substance-Related Disorders Work Group considered these issues and recommended revisions for DSM-5. General concerns included whether to retain the division into two main disorders (dependence and abuse), whether substance use disorder criteria should be added or removed, and whether an appropriate substance use disorder severity indicator could be identified. Specific issues included possible addition of withdrawal syndromes for several substances, alignment of nicotine criteria with those for other substances, addition of biomarkers, and inclusion of nonsubstance, behavioral addictions.
This article presents the major issues and evidence considered by the work group, which included literature reviews and extensive new data analyses. The work group recommendations for DSM-5 revisions included combining abuse and dependence criteria into a single substance use disorder based on consistent findings from over 200,000 study participants, dropping legal problems and adding craving as criteria, adding cannabis and caffeine withdrawal syndromes, aligning tobacco use disorder criteria with other substance use disorders, and moving gambling disorders to the chapter formerly reserved for substance-related disorders. The proposed changes overcome many problems, while further studies will be needed to address issues for which less data were available.
doi:10.1176/appi.ajp.2013.12060782
PMCID: PMC3767415  PMID: 23903334
7.  Predictors of Initial and Sustained Remission from Alcohol Use Disorders: Findings from the 30-Year Follow-Up of the San Diego Prospective Study 
Background
Individuals who report problematic drinking early in life often recover from alcohol-related disorders, with or without formal treatment. While risk factors associated with developing alcohol use disorders (AUDs), such as a family history (FH) of alcoholism and the genetically-influenced low level of response (LR) to alcohol, have been identified, less is known about characteristics that relate to remission from AUDs.
Methods
The male subjects (98% Caucasian) for this study were 129 probands from the San Diego Prospective Study who were first evaluated at age 20 as drinking but not alcohol dependent young men, most of whom were college graduates by followup. The individuals evaluated here met criteria for an AUD at their first follow-up at age 28 to 33 and were followed every 5 years for the next two decades. Discrete-time survival analysis was used to examine rates of initial and sustained AUD remission and to evaluate the relationships of premorbid characteristics and other risk factors to these outcomes.
Results
60% of the sample met criteria for an initial AUD remission of five or more years, including 45% with sustained remission (i.e. no subsequent AUD diagnosis). Higher education, lower drinking frequency, and having a diagnosis of alcohol abuse (rather than dependence) were associated with higher rates of initial AUD remission. A lower LR to alcohol at age 20, as well as lower drinking frequency, having received formal alcohol treatment, and older age at the first follow-up all predicted a greater likelihood of sustained AUD remission.
Conclusion
This study identified key factors associated with initial and sustained AUD remission in subjects diagnosed with AUD in young adulthood. Characteristics associated with better outcomes early in the lifespan, such as lower drinking frequency and early treatment appear to have a lasting impact on remission from AUD across adulthood.
doi:10.1111/acer.12107
PMCID: PMC3675188  PMID: 23458300
Level of Response; Alcoholism; Survival Analysis; Longitudinal; Remission
8.  Common biological networks underlie genetic risk for alcoholism in African- and European-American populations 
Genes, brain, and behavior  2013;12(5):532-542.
Alcohol dependence (AD) is a heritable substance addiction with adverse physical and psychological consequences, representing a major health and economic burden on societies worldwide. Genes thus far implicated via linkage, candidate gene and genome-wide association studies (GWAS) account for only a small fraction of its overall risk, with effects varying across ethnic groups. Here we investigate the genetic architecture of alcoholism and report on the extent to which common, genome-wide SNPs collectively account for risk of AD in two US populations, African-Americans (AAs) and European-Americans (EAs). Analyzing GWAS data for two independent case-control sample sets, we compute polymarker scores that are significantly associated with alcoholism (P=1.64 × 10−3 and 2.08 × 10−4 for EAs and AAs, respectively), reflecting the small individual effects of thousands of variants derived from patterns of allelic architecture that are population-specific. Simulations show that disease models based on rare and uncommon causal variants (MAF<0.05) best fit the observed distribution of polymarker signals. When scoring bins were annotated for gene location and examined for constituent biological networks, gene enrichment is observed for several cellular processes and functions in both EA and AA populations, transcending their underlying allelic differences. Our results reveal key insights into the complex etiology of AD, raising the possibility of an important role for rare and uncommon variants, and identify polygenic mechanisms that encompass a spectrum of disease liability, with some, such as chloride transporters and glycine metabolism genes, displaying subtle, modifying effects that are likely to escape detection in most GWAS designs.
doi:10.1111/gbb.12043
PMCID: PMC3709451  PMID: 23607416
alcohol dependence; GWAS; polymarker scores; synthetic association; rare variants; pathway analysis
9.  A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53 
Molecular psychiatry  2012;18(11):10.1038/mp.2012.143.
Several studies have identified genes associated with alcohol use disorders, but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism (COGA) to identify novel genes affecting risk for alcohol dependence. To maximize the power of the extended family design we used a quantitative endophenotype, measured in all individuals: number of alcohol dependence symptoms endorsed (symptom count). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with symptom count were also associated with the dichotomous phenotype, DSM-IV alcohol dependence. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol (p=4.5×10−8, inflation corrected p=9.4×10−7). Results with DSM-IV alcohol dependence in the regions of interest support our findings with symptom count, though the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: non-overlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian twin-family study of alcohol use disorders (OZALC). Nominal association of C15orf53 with symptom count was observed in SAGE. The variant that showed strongest association with symptom count, rs12912251 and its highly correlated variants (D′=1, r2≥ 0.95), has previously been associated with risk for bipolar disorder.
doi:10.1038/mp.2012.143
PMCID: PMC3752321  PMID: 23089632
DSM-IV alcohol dependence symptoms; Family-based GWAS; C15orf53; Quantitative traits
10.  Stability of Scores and Correlations with Drinking Behaviors Over 15 Years for the Self-Report of the Effects of Alcohol Questionnaire 
Drug and alcohol dependence  2012;128(3):194-199.
Background
The low level of response (LR) to alcohol is an endophenotype that predicts future heavy drinking and alcohol use disorders (AUDs). LR can be measured by laboratory-based alcohol challenges or by the retrospective Self-Report of the Effects of Alcohol (SRE) questionnaire. This paper reports the relationships among these two measures and how each related to both recent and future drinking quantities and problems across 15 years in 235 men.
Methods
Probands from the San Diego Prospective Study (SDPS) participated in alcohol challenges to determine their LR at age 20, and subsequently at ages 35, 40, 45 and 50 filled out an SRE regarding the number of standard drinks needed for up to four effects early in life (SRE5) and across early, recent, and heaviest drinking life epochs (SRET). Changes in SRE scores across time were evaluated with ANOVAs and Pearson correlations were used to evaluate how SRE5, SRET and earlier alcohol challenge-based LRs related to prior five-year drinking histories and future alcohol involvement.
Results
While SRE scores decreased 9% over the 15 years, the relationships between SRE values with prior five-year drinking parameters and with future alcohol intake and problems remained robust, and even improved with advancing age. A similar pattern was seen for correlations between SRE and alcohol challenge-based LRs 15 to 30 years previously.
Conclusions
Alcohol challenge and SRE-based LRs related to each other, to alcohol use patterns, and to future alcohol problems across age 35 to 50 in the men studied here.
doi:10.1016/j.drugalcdep.2012.08.022
PMCID: PMC3537846  PMID: 22980675
alcohol; alcohol sensitivity; alcohol course; predictors
11.  Genetic influences on craving for alcohol 
Addictive behaviors  2012;38(2):1501-1508.
Introduction
Craving is being considered for inclusion in the Diagnostic and Statistical Manual (DSM) DSM-5. However, little is known of its genetic underpinnings – specifically, whether genetic influences on craving are distinct from those influencing DSM-IV alcohol dependence.
Method
Analyses were conducted in a sample of unrelated adults ascertained for alcohol dependence (N=3976). Factor analysis was performed to examine how alcohol craving loaded with the existing DSM-IV alcohol dependence criteria. For genetic analyses, we first examined whether genes in the dopamine pathway, including dopamine receptor genes (DRD1, DRD2, DRD3, DRD4) and the dopamine transporter gene (SLC6A3), which have been implicated in neurobiological studies of craving, as well as alpha-synuclein (SNCA), which has been previously found to be associated with craving, were associated with alcohol craving in this sample. Second, in an effort to identify novel genetic variants associated with craving, we conducted a genomewide association study (GWAS). For variants that were implicated in the primary analysis of craving, we conducted additional comparisons - to determine if these variants were uniquely associated with alcohol craving as compared with alcohol dependence. We contrasted our results to those obtained for DSM-IV alcohol dependence, and also compared alcohol dependent individuals without craving to non-dependent individuals who also did not crave alcohol.
Results
Twenty-one percent of the full sample reported craving alcohol. Of those reporting craving, 97.3% met criteria for DSM-IV alcohol dependence with 48% endorsing all 7 dependence criteria. Factor analysis found a high factor loading (0.89) for alcohol craving. When examining genes in the dopamine pathway, single nucleotide polymorphisms (SNPs) in DRD3 and SNCA were associated with craving (p<0.05). There was evidence for association of these SNPs with DSM-IV alcohol dependence (p<0.05) but less evidence for dependence without craving (p>0.05), suggesting that the association was due in part to craving. In the GWAS, the greatest evidence of association with craving was for a SNP in the integrin alpha D (ITGAD) gene on chromosome 7 (rs2454908; p=1.8×10−6). The corresponding p-value for this SNP with DSM-IV alcohol dependence was similar (p=4.0×10−5) but was far less with dependence without craving (p=0.02), again suggesting the association was due to alcohol craving. Adjusting for dependence severity (number of endorsed criteria) attenuated p-values but did not eliminate association.
Conclusions
Craving is frequently reported by those who report multiple other alcohol dependence symptoms. We found that genes providing evidence of association with craving were also associated with alcohol dependence; however, these same SNPs were not associated with alcohol dependence in the absence of alcohol craving. These results suggest that there may be unique genetic factors affecting craving among those with alcohol dependence.
doi:10.1016/j.addbeh.2012.03.021
PMCID: PMC3394913  PMID: 22481050
12.  A Model to Determine the Likely Age of an Adolescent’s First Drink of Alcohol 
Pediatrics  2013;131(2):242-248.
OBJECTIVE:
With the use of a new cohort of adolescent subjects, predictors from the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) interview and the Achenbach Youth Self Report (YSR) were combined to model age of first drink (AFD).
METHODS:
Subjects consisted of 820 adolescents (ages 14–17) drawn from the current phase of the Collaborative Study on the Genetics of Alcoholism. Three Cox proportional hazards models were considered. Model 1 contained SSAGA variables equivalent to AFD predictors from our previous study: interview age, family history of alcohol dependence, and number of conduct disorder symptoms. Model 2 incorporated 2 additional SSAGA questions (best friends drink and smoked a cigarette before a reported AFD) plus 8 YSR-derived scale scores. Model 3 was a reduced version of model 2, retaining only significant predictors.
RESULTS:
Model 2 was a significant improvement over model 1. Model 3 was the best and the most parsimonious of the 3 with respect to likelihood ratio and Wald χ2 tests and retained only 5 variables from model 2. Included variables were the following: (1) best friends drink, (2) membership in a high-risk alcohol dependence family, (3) number of conduct disorder symptoms, (4) YSR externalizing score, and (5) YSR social problems score.
CONCLUSIONS:
Adding variables to those from our original study improved our ability to model the likely age of alcohol initiation. In addition to the SSAGA, the YSR appears to have utility as a research tool to predict the age of alcohol initiation.
doi:10.1542/peds.2012-0880
PMCID: PMC3557403  PMID: 23296431
alcohol/drug use; age of first use; predictor variables; modeling age of first use
13.  How Phenotype and Developmental Stage Affect the Genes We Find: GABRA2 and Impulsivity 
Context
The detection and replication of genes involved in psychiatric outcome has been notoriously difficult. Phenotypic measurement has been offered as one explanation, although most of this discussion has focused on problems with binary diagnoses.
Objective
This article focuses on two additional components of phenotypic measurement that deserve further consideration in evaluating genetic associations: (1) the measure used to reflect the outcome of interest, and (2) the developmental stage of the study population. We focus our discussion of these issues around the construct of impulsivity and externalizing disorders, and the association of these measures with a specific gene, GABRA2.
Design, Setting, and Participants
Data were analyzed from the Collaborative Study on the Genetics of Alcoholism Phase IV assessment of adolescents and young adults (ages 12–26; N = 2,128).
Main Outcome Measures
Alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder symptoms were measured by psychiatric interview; Achenbach youth/adult self-report externalizing scale; Zuckerman Sensation-Seeking scale; Barratt Impulsivity scale; NEO extraversion and consciousness.
Results
GABRA2 was associated with subclinical levels of externalizing behavior as measured by the Achenbach in both the adolescent and young adult samples. Contrary to previous associations in adult samples, it was not associated with clinical-level DSM symptom counts of any externalizing disorders in these younger samples. There was also association with sensation-seeking and extraversion, but only in the adolescent sample. There was no association with the Barratt impulsivity scale or conscientiousness.
Conclusions
Our results suggest that the pathway by which GABRA2 initially confers risk for eventual alcohol problems begins with a predisposition to sensation-seeking early in adolescence. The findings support the heterogeneous nature of impulsivity and demonstrate that both the measure used to assess a construct of interest and the age of the participants can have profound implications for the detection of genetic associations.
doi:10.1017/thg.2013.20
PMCID: PMC3663593  PMID: 23561058
GABRA2; association; impulsivity; sensation-seeking; externalizing; adolescence
14.  High versus Low Level of Response to Alcohol: Evidence of Differential Reactivity to Emotional Stimuli 
Biological psychiatry  2012;72(10):848-855.
Background
The low level of response (LR) or sensitivity to alcohol is genetically influenced and predicts heavy drinking and alcohol problems. Functional magnetic resonance imaging (fMRI) studies using cognitive tasks suggest that subjects with a low LR process cognitive information differently after placebo and alcohol than those with a high LR, but no studies have evaluated if similar LR group differences are seen during an emotional processing task.
Methods
fMRI data were gathered from 116 non-alcoholic subjects (60 women) following oral placebo or ~0.7 ml/kg of ethanol while performing a modified emotional faces processing task. These included 58 low- and high-LR pairs matched on demography and aspects of substance use.
Results
Blood alcohol levels and task performance were similar across LR groups, but low LR subjects consumed ~ 0.8 drinks more per occasion. Thirteen brain regions (mostly the middle and inferior frontal gyri, cingulate, and insula) showed significant LR group or LR by placebo/alcohol condition interactions for emotional (mostly happy) faces relative to non-face trials. Low LR subjects generally showed decreasing BOLD response contrasts across placebo to alcohol, while high LR showed increasing contrasts from placebo to alcohol, even after controlling for drinking quantities and alcohol-related changes in cerebral blood flow.
Conclusions
Thus, LR group fMRI differences are as prominent during an emotional face task as during cognitive paradigms. Low LR individuals processed both types of information in a manner that might contribute to an impaired ability to recognize modest levels of alcohol intoxication in a range of life situations.
doi:10.1016/j.biopsych.2012.04.016
PMCID: PMC3433640  PMID: 22608014
fMRI; alcohol sensitivity; emotional stimuli; fear; Hariri; alcoholism
15.  A Systematic SNP Screen to Fine-Map Alcohol Dependence Genes on Chromosome 7 Identifies Association with a Novel Susceptibility Gene ACN9 
Biological psychiatry  2007;63(11):10.1016/j.biopsych.2007.11.005.
Background
Chromosome 7 has shown consistent evidence of linkage with a variety of phenotypes related to alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) project. Using a sample of 262 densely affected families, a peak lod score for alcohol dependence of 2.9 was observed at D7S1799 (Wang et al., 2004, Hum Mol Genet). The lod score in the region increased to 4.1 when a subset of the sample was genotyped with the Illumina Linkage III panel for the Genetic Analysis Workshop 14 (GAW14; Dunn et al., 2005, BMC Genetics). To follow-up on this linkage region, we systematically screened SNPs across a 2 LOD support interval surrounding the alcohol dependence peak.
Methods
SNPs were selected from the HapMap Phase I CEPH data to tag linkage disequilibrium bins across the region. 1340 across the 18Mb region, genotyped by the Center for Inherited Disease Research (CIDR), were analyzed. Family-based association analyses were performed on a sample of 1172 individuals from 217 Caucasian families. Results: Eight SNPs showed association with alcohol dependence at p<0.01. Four of the eight most significant SNPs were located in or very near the ACN9 gene. We conducted additional genotyping across ACN9 and identified multiple variants with significant evidence of association with alcohol dependence.
Conclusions
These analyses suggest that ACN9 is involved in the predisposition to alcohol dependence. Data from yeast suggest that ACN9 is involved in gluconeogenesis and the assimilation of ethanol or acetate into carbohydrate.
doi:10.1016/j.biopsych.2007.11.005
PMCID: PMC3823371  PMID: 18163977
genetics; association; linkage disequilibrium; alcohol dependence; ACN9
16.  CHRNB3 is more strongly associated with FTCD-based nicotine dependence than cigarettes per day: phenotype definition changes GWAS results 
Addiction (Abingdon, England)  2012;107(11):2019-2028.
Aims
Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e. CPD versus Fagerström Test for Cigarette Dependence (FTCD) score as a measure of nicotine dependence) on genome-wide association studies of nicotine dependence.
Design
Genome-wide association study
Setting
Community sample
Participants
A total of 3,365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2,267 were European Americans,999 were African Americans.
Measurements
Nicotine dependence defined by FTCD score ≥4, CPD
Findings
The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 (OR=0.65, p=2.4×10−8). This association was further strengthened in a meta-analysis with a previously published dataset (combined p=6.7 ×10−16, total n=4,200).When CPD was used as an alternate phenotype, the association no longer reached genome-wide significance (β=−0.08, p=0.0007).
Conclusions
Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence (FTCD) show different associations with polymorphisms in genetic loci.
doi:10.1111/j.1360-0443.2012.03922.x
PMCID: PMC3427406  PMID: 22524403
17.  Sex differences in how a low sensitivity to alcohol relates to later heavy drinking 
Drug and alcohol review  2012;31(7):871-880.
Introduction and Aims
A low level of response (LR), or low sensitivity, to alcohol is a genetically-influenced characteristic that predicts future heavy drinking and alcohol problems. While previous analyses of how LR relates to heavier drinking reported the process is similar in males and females, some potential sex differences have been identified. This difference is further explored in these analyses.
Design and Methods
Prospective structural equation models (SEMs) were evaluated for 183 young adult females and 162 males, none of Asian background, from the Collaborative Study on the Genetics of Alcoholism (COGA). Invariance analyses and SEM evaluations by sex were used to compare across females and males for these primarily Caucasian (75%), non-Asian young (mean age 19) subjects.
Results
The prospective SEM for the full set of 345 subjects had good fit characteristics and explained 37% of the variance. While the initial invariance analyses identified few sex differences, comparisons of correlations and direct evaluations of path coefficients across males and females indicated that only females showed a link between a low LR and future alcohol problems that was partially mediated by more positive alcohol expectancies and drinking to cope. These sex differences were reflected in the different structures of the SEM results for female vs. male subjects.
Discussion and Conclusions
These prospective results indicate that there might be some important sex differences regarding how a lower LR relates to alcohol outcomes that should be considered in protocols focusing on preventing the impact of LR on future drinking problems.
doi:10.1111/j.1465-3362.2012.00469.x
PMCID: PMC3459074  PMID: 22708705
drinking; alcoholism; sex; genetics; structural equation models
18.  Acute Ethanol Effects on Brain Activation in Low- and High-Level Responders to Alcohol 
Background
A low level of response (LR) to alcohol is an important endophenotype associated with an increased risk for alcoholism. However, little is known about how neural functioning may differ between individuals with low and high LRs to alcohol. This study examined whether LR group effects on neural activity varied as a function of acute alcohol consumption.
Methods
30 matched high- and low-LR pairs (N=60 healthy young adults) were recruited from the University of California, San Diego and administered a structured diagnostic interview and laboratory alcohol challenge followed by two fMRI sessions under placebo and alcohol conditions, in randomized order. Task performance and BOLD response contrast to high relative to low working memory load in an event-related visual working memory (VWM) task was examined across 120 fMRI sessions.
Results
Both LR groups performed similarly on the VWM task across conditions. A significant LR group by condition interaction effect was observed in inferior frontal and cingulate regions, such that alcohol attenuated the LR group differences found under placebo (p<.05). The LR group by condition effect remained even after controlling for cerebral blood flow, age, and typical drinking quantity.
Conclusions
Alcohol had differential effects on brain activation for low and high LR individuals within frontal and cingulate regions. These findings represent an additional step in the search for physiological correlates of a low LR, and identify brain regions that may be associated with the low LR response.
doi:10.1111/j.1530-0277.2010.01193.x
PMCID: PMC3774836  PMID: 20477775
Level of response; fMRI; visual working memory; cerebral blood flow
19.  Copy number variations in 6q14.1 and 5q13.2 are associated with alcohol dependence 
Background
Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between DSM-IV alcohol dependence and all common copy number variations (CNV) with good reliability in the Study of Addiction: Genetics and Environment (SAGE).
Methods
All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), as a part of three contributing studies. 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVpartition, PennCNV and QuantiSNP and only CNVs identified by all three software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory.
Results
CNVs in 6q14.1 (P= 1.04 × 10−6) and 5q13.2 (P= 3.37 × 10−4) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2 there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation, and language delay. The CNV in 5q13.2 was validated whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution.
Conclusion
This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence.
doi:10.1111/j.1530-0277.2012.01758.x
PMCID: PMC3436997  PMID: 22702843
Copy Number Variations; Alcohol dependence; CNV Accuracy
21.  Family-based Genome-wide Association Study of Frontal Theta Oscillations Identifies Potassium Channel Gene KCNJ6 
Genes, brain, and behavior  2012;11(6):712-719.
Event-related oscillations (EROs) represent highly heritable neuroelectric correlates of cognitive processes that manifest deficits in alcoholics and in offspring at high risk to develop alcoholism. Theta ERO to targets in the visual oddball task has been shown to be an endophenotype for alcoholism. A family-based genome-wide association study was performed for the frontal theta ERO phenotype using 634583 autosomal single nucleotide polymorphisms (SNPs) genotyped in 1560 family members from 117 families densely affected by alcohol use disorders, recruited in the Collaborative Study on the Genetics of Alcoholism. Genome-wide significant association was found with several SNPs on chromosome 21 in KCNJ6 (a potassium inward rectifier channel; KIR3.2/GIRK2), with the most significant SNP at P = 4.7 × 10-10). The same SNPs were also associated with EROs from central and parietal electrodes, but with less significance, suggesting that the association is frontally focused. One imputed synonymous SNP in exon 4, highly correlated with our top three SNPs, was significantly associated with the frontal theta ERO phenotype. These results suggest KCNJ6 or its product GIRK2 account for some of the variations in frontal theta band oscillations. GIRK2 receptor activation contributes to slow inhibitory postsynaptic potentials that modulate neuronal excitability, and therefore influence neuronal networks.
doi:10.1111/j.1601-183X.2012.00803.x
PMCID: PMC3666338  PMID: 22554406
22.  Dosage Transmission Disequilibrium Test (dTDT) for Linkage and Association Detection 
PLoS ONE  2013;8(5):e63526.
Both linkage and association studies have been successfully applied to identify disease susceptibility genes with genetic markers such as microsatellites and Single Nucleotide Polymorphisms (SNPs). As one of the traditional family-based studies, the Transmission/Disequilibrium Test (TDT) measures the over-transmission of an allele in a trio from its heterozygous parents to the affected offspring and can be potentially useful to identify genetic determinants for complex disorders. However, there is reduced information when complete trio information is unavailable. In this study, we developed a novel approach to “infer” the transmission of SNPs by combining both the linkage and association data, which uses microsatellite markers from families informative for linkage together with SNP markers from the offspring who are genotyped for both linkage and a Genome-Wide Association Study (GWAS). We generalized the traditional TDT to process these inferred dosage probabilities, which we name as the dosage-TDT (dTDT). For evaluation purpose, we developed a simulation procedure to assess its operating characteristics. We applied the dTDT to the simulated data and documented the power of the dTDT under a number of different realistic scenarios. Finally, we applied our methods to a family study of alcohol dependence (COGA) and performed individual genotyping on complete families for the top signals. One SNP (rs4903712 on chromosome 14) remained significant after correcting for multiple testing Methods developed in this study can be adapted to other platforms and will have widespread applicability in genomic research when case-control GWAS data are collected in families with existing linkage data.
doi:10.1371/journal.pone.0063526
PMCID: PMC3653954  PMID: 23691058
23.  Priming deficiency in male subjects at risk for alcoholism: the N4 during a lexical decision task 
Background
While there is extensive literature on the relationship between the P3 component of event-related potentials (ERPs) and risk for alcoholism, there are few published studies regarding other potentially important ERP components. One important candidate is the N4(00) component in the context of semantic processing, as abnormalities in this component have been reported for adult alcoholics.
Method
A semantic priming task was administered to non-alcohol dependent male offspring (18 to 25 years) of alcoholic fathers [high risk (HR) n=23] and non-alcoholic fathers [low risk (LR) n=28], to study whether the two groups differ in terms of the N4 component. Subjects were presented with 150 words and 150 non-words. Among the words, 50 words (primed) were preceded by their antonyms (prime, n=50), whereas the remaining 50 words were unprimed. For the analysis, N4 amplitude and latency, as well as behavioral measures for the primed and unprimed words were considered.
Results
A significant interaction effect was observed between semantic condition and group, where HR subjects did not show N4 attenuation for primed stimuli.
Conclusion
The lack of N4 attenuation to primed stimuli and/or inability to differentiate between primed and unprimed stimuli, without latency and reaction time being affected, suggest deficits in semantic priming, especially in semantic expectancy and/or post-lexical semantic processing in HR male offspring. Further, it indicates that it might be an electrophysiological endophenotype that reflects genetic vulnerability to develop alcoholism.
doi:10.1111/j.1530-0277.2009.01042.x
PMCID: PMC3601897  PMID: 19764939
Semantic priming; N4; alcoholism; high risk; endophenotype
24.  Evidence for Genes on Chromosome 2 Contributing to Alcohol Dependence With Conduct Disorder and Suicide Attempts 
Twin studies provide strong evidence that there is a shared genetic liability that predisposes to a number of different psychiatric outcomes related to behavioral disinhibition. Further, alcohol dependence comorbid with other disinhibitory disorders is particularly heritable. Chromosome 2p14–2q14.3 has been linked to multiple psychiatric conditions related to behavioral undercontrol. In the Collaborative Study on the Genetics of Alcoholism (COGA), we previously reported linkage to this region with alcohol dependence (AD), suicide attempts (SUI), and conduct disorder (CD). In this study, we follow-up on these previous reports of linkage by combining the phenotypes in analyses that jointly consider the presence of multiple conditions. Linkage analyses of the combined phenotype of AD with CD or SUI results in a maximum LOD score of 5.4 in this region. In addition to this primary linkage peak, independent samples have reported linkage to other alcohol-related phenotypes across chromosome 2. Accordingly, we followed-up these linkage signals by testing for association with SNPs across chromosome 2 in a case–control sample, in which a subset of the cases consisted of alcohol-dependent probands from the linkage sample. We find evidence of association with the combined AD with CD or SUI phenotype, with 23 genes surviving permutation testing. The number of associated genes across the chromosome may explain the persistent linkage findings reported on chromosome 2 across a number of independent studies of alcohol and disinhibitory phenotypes. Further, none of the genes were located directly under the primary COGA linkage peak, which has implications for association tests following-up linkage peaks.
doi:10.1002/ajmg.b.31089
PMCID: PMC3597340  PMID: 20468071
alcoholism; genetics; linkage; association; behavioral disinhibition
25.  Genome-wide association study of comorbid depressive syndrome and alcohol dependence 
Psychiatric genetics  2012;22(1):31-41.
Objective
Depression and alcohol dependence are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35–60%. In addition, evidence from twin studies suggests that alcohol dependence and depression are genetically correlated. Here we report results from a genome-wide association study (GWAS) of a comorbid phenotype in which cases meet the DSM-IV symptom threshold for major depressive symptomatology and DSM-IV criteria for alcohol dependence.
Methods
Samples (N=467 cases and N=407 controls) were of European-American descent, and were genotyped using the Illumina Human 1M BeadChip array.
Results
Although no SNP meets genome-wide significance criteria, we identify ten markers with p-values < 1 × 10−5, seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding p<1 × 10−3 are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, alcohol dependence, or other addiction-related phenotypes – such as CDH13, CSMD2, GRID1, and HTR1B – were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an alcohol dependence-only phenotype is modest.
Conclusions
These results underscore the complex genomic influences on psychiatric phenotypes, and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect alcohol dependence alone.
doi:10.1097/YPG.0b013e32834acd07
PMCID: PMC3241912  PMID: 22064162
genetics of alcoholism; comorbidity; genetic risk; depressive syndrome

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